Selective anti-malarial minor groove binders
Selective anti-malarial minor groove binders
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DOI：
10.1016/j.bmcl.2016.05.039
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发表时间：
2016-07-15
影响因子：
2.7
通讯作者：
Suckling, Colin J.
中科院分区：
文献类型：
--
作者：
Scott, Fraser J.;Khalaf, Abedawn I.;Suckling, Colin J.
利用氯喹敏感株（3D 7）和氯喹抗性株（Dd 2）与人胚肾（HEK）细胞作为哺乳动物细胞毒性的指标进行比较，评价了一组31种具有不同结构特征的DNA小沟结合物（MGB）作为治疗恶性疟原虫感染的潜在药物。在两个N-末端结构单元之间具有烯烃连接的MGB被证明是最有活性的，IC 50值在30-500 nM范围内，治疗比率在10->500范围内。许多活性化合物含有C-烷基噻唑结构单元。鉴定出logD（7.4）值约为3或7的活性化合物。重要的是，测试的MGB对氯喹敏感和抗性菌株基本上同样有效。结果表明，适当设计的MGBs有潜力发展成为临床候选抗疟药物有效对抗疟原虫耐药菌株。(C)2016爱思唯尔有限公司版权所有
A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30-500 nM and therapeutic ratios in the range 10->500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD(7.4) values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia. (C) 2016 Elsevier Ltd. All rights reserved.